BBB proteomic analysis reveals that complex febrile seizures in infancy enhance susceptibility to epilepsy in adulthood through dysregulation of ECM-receptor interaction signaling pathway.

IF 5.9 1区 医学 Q1 NEUROSCIENCES
Qian Wang, Liangyu Pan, Siruan Chen, Yuyu Zhang, Guangyuan Liu, Yiying Wu, Xia Qin, Panpan Zhang, Wei Zhang, Jianghua Zhang, Dezhi Kong
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引用次数: 0

Abstract

Background: Complex febrile seizures (CFS) have been associated with an increased risk of epilepsy in adulthood. However, the specific link between blood-brain barrier (BBB) and the predisposition to epilepsy in adults who experienced CFS during infancy remains unclear. The objective of this study was to investigate the alteration of BBB in adult mice who had experienced CFS during infancy, and to explore the mechanisms of increased susceptibility to epilepsy after CFS.

Methods: The CFS pup model was induced using hot air, and the seizure susceptibility was examined using low-dose pentylenetetrazole (PTZ) after 8 W. The brain microvessels representing BBB function were isolated and their protein expression changes were analyzed using data-independent acquisition (DIA) proteomic techniques. Subsequently, the bioinformatic analyses were performed using ClusterProfiler, STRING, Gene Set Enrichment Analysis (GSEA), etc. The enriched pathways, changes in the expression of BBB-related proteins, and alterations in metabolites including certain neurotransmitters were subsequently validated by Western Blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and mass spectrometric imaging (MSI). In addition, we selected the MMP inhibitor Incyclinide to verify that dysregulation of the ECM-receptor interaction signaling pathway increases epilepsy susceptibility in adult mice.

Results: Mice that experienced CFS in infancy show increased susceptibility to epilepsy in adulthood, and BBB proteomic profile was significantly altered in the CFS mice. The network analysis suggests that dysregulation of the extracellular matrix (ECM)-receptor interaction pathway is a key mechanism. Moreover, MSI analysis uncovered notable changes in differential metabolites, including amino acids and nucleotide-derived neurotransmitters associated with the function of BBB maintaining neuronal homeostasis. Subsequent validation experiments showed that dysregulation of the ECM-receptor interaction signaling pathway exacerbated epilepsy susceptibility in adult mice.

Conclusion: Our research represents the pioneering demonstration of the modified BBB proteomics associated with epilepsy susceptibility in adult mice previously exposed to CFS in infancy. Notably, the increased susceptibility is attributed to the dysregulation of the ECM-receptor interaction pathway. These findings may help to elucidate the role of BBB alterations in the progression of epilepsy susceptibility, and provide new orientations for subsequent prevention and treatment of epilepsy.

血脑屏障蛋白质组学分析表明,婴儿期复杂的热性惊厥通过ecm受体相互作用信号通路的失调而增加成年期癫痫的易感性。
背景:复杂发热性癫痫发作(CFS)与成年期癫痫风险增加有关。然而,在婴儿期经历CFS的成人中,血脑屏障(BBB)与癫痫易感性之间的具体联系尚不清楚。本研究旨在探讨婴儿期CFS成年小鼠血脑屏障的改变,并探讨CFS后癫痫易感性增加的机制。方法:采用热空气诱导CFS幼犬模型,8w后采用低剂量戊四唑(PTZ)检测癫痫发作敏感性。分离代表血脑屏障功能的脑微血管,采用数据独立采集(DIA)蛋白质组学技术分析其蛋白表达变化。随后,使用ClusterProfiler、STRING、Gene Set Enrichment Analysis (GSEA)等进行生物信息学分析。随后,通过Western Blotting、定量实时聚合酶链反应(qRT-PCR)和质谱成像(MSI)验证了富集通路、血脑屏障相关蛋白表达的变化以及代谢物(包括某些神经递质)的改变。此外,我们选择了MMP抑制剂Incyclinide来验证ecm受体相互作用信号通路的失调会增加成年小鼠的癫痫易感性。结果:婴儿期经历CFS的小鼠在成年期对癫痫的易感性增加,并且CFS小鼠的血脑屏障蛋白质组谱显着改变。网络分析表明,细胞外基质(ECM)-受体相互作用途径的失调是其关键机制。此外,MSI分析揭示了差异代谢物的显著变化,包括与血脑屏障维持神经元稳态功能相关的氨基酸和核苷酸衍生的神经递质。随后的验证实验表明,ecm受体相互作用信号通路的失调加剧了成年小鼠的癫痫易感性。结论:我们的研究开创性地证明了在婴儿期暴露于CFS的成年小鼠中,修饰的血脑屏障蛋白质组学与癫痫易感性相关。值得注意的是,易感性的增加归因于ecm受体相互作用途径的失调。这些发现可能有助于阐明血脑屏障改变在癫痫易感性进展中的作用,并为癫痫的后续预防和治疗提供新的方向。
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来源期刊
Fluids and Barriers of the CNS
Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience
CiteScore
10.70
自引率
8.20%
发文量
94
审稿时长
14 weeks
期刊介绍: "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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